(526d) Evaluation of Biocompatibility of Novel Block Copolymer Gels/Micelles As Potential Vaccine Adjuvants

Evaluation of biocompatibility of novel block copolymer gels/micelles
as potential vaccine adjuvants

Justin R. Adams¹, Sujata Senapati¹,
Michael J. Wannemuehler², Balaji
Narasimhan¹, Surya Mallapragada¹

¹Chemical
& Biological Engineering; ²Veterinary Microbiology and
Preventive Medicine;

Iowa State University, Ames, IA

In
addition to being delivery systems for antigens, an ideal adjuvant should be
able to modulate an effective innate immune response and enhance the induction
of long-lasting immunity. Adjuvant platforms may also allow for fewer doses
required and less invasive routes of vaccine administration. Even after decades
of research, presently only a few vaccine adjuvants, such as, alum and oil in
water emulsion, are approved for safe human usage. However, vaccines adjuvanted with these compounds have long been associated
with inflammation at the injection site. Therefore, it is essential to discard
the practice of using off-the-shelf adjuvants for vaccines and move towards the
design and implementation of novel vaccine adjuvants. Biocompatible polymers
have been recently investigated as novel adjuvants and delivery systems for
next generation vaccines. However, as research into new polymeric adjuvants
progresses, the safety of these compounds is of great concern. There is a need
to balance the immunomodulatory properties of vaccine
adjuvants with the desire to improve patient compliance by avoiding adverse
reactions such as pain, redness, and swelling (i.e., reactogenicity)
at the site of administration.

Amphiphilic block copolymers have been used for
applications in gene therapy and drug delivery in vivo. Our research group has previously synthesized cationic pentablock copolymers following a new method of catalysis
for atom transfer radical polymerization (ATRP), which significantly reduces in vitro cellular toxicity of the
polymer. These pentablock copolymers are composed of
FDA approved Pluronic F127 and pendant amine groups
of poly(2-diethylaminoethylmethacrylate) with reversible micelle and gel
formation capabilities in response to external stimuli such as temperature and/or
pH. In the micellar phase, these
pentablock copolymer can act as a cargo hold for
various protein payloads allowing for sustained release of the antigen.

In
this work, we investigate the safety and biocompatibility of the pentablock copolymer gels/micelles in a murine model. This
study included serum and urine analysis, assessment of inflammation at the injection
site, proinflammatory cytokine analysis, and histopathological analysis. Mice were subcutaneously
immunized with micelle/gel formulations and were compared to separate groups of
mice treated with saline or incomplete FreundÕs adjuvant (IFA).  For the urinalysis, little to no
statistical difference in the quantity of creatinine in urine of mice
administered with the pentablock copolymer
formulations was observed when compared to the saline alone group. The histopathological studies of the administration site
tissue, kidney, and liver showed no adverse reactions. Using a live animal
imager, local inflammation was assessed and was shown to be markedly less inflammatory
post-administration of the block copolymer when compared to IFA.

Combined
with previous studies demonstrating the induction of robust humoral immunity in
mice, the results of this study highlight the safety and adjuvanticity
of the pentablock copolymer micelle/gel vaccine delivery
platform.